Trehalose inhibits H(2)O(2)-induced autophagic death in dopaminergic SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation

Autophagy is a catabolic process to maintain intracellular homeostasis via removal of cytoplasmic macromolecules and damaged cellular organelles through lysosome-mediated degradation. Trehalose is often regarded as an autophagy inducer, but we reported previously that it could prevent ischemic insults-induced autophagic death in neurons. Thus, we further investigated in this study whether trehalose could protect human dopaminergic SH-SY5Y cells against H(2)O(2)-induced lethal autophagy. We found pretreatment with trehalose not only prevented H(2)O(2)-induced death in SH-SY5Y cells, but also reversed H(2)O(2)-induced upregulation of LC3II, Beclin1 and ATG5 and downregulation of p62. Then, we proved that either autophagy inhibitor 3MA or genetic knockdown of ATG5 prevented H(2)O(2)-triggered death in SH-SY5Y cells. These indicated that trehalose could inhibit H(2)O(2)-induced autophagic death in SH-SY5Y cells. Further, we found that trehalose inhibited H(2)O(2)-induced AMPK activation and endoplasmic reticulum (ER) stress. Moreover, inhibition of AMPK activation with compound C or alleviation of ER stress with chemical chaperone 4-PBA obviously attenuated H(2)O(2)-induced changes in autophagy-related proteins. Notably, we found that trehalose inhibited H(2)O(2)-induced increase of intracellular ROS and reduction in the activities of CAT and SOD. Consistently, our data revealed as well that mitigation of intracellular ROS levels with antioxidant NAC markedly attenuated H(2)O(2)-induced AMPK activation and ER stress. Therefore, we demonstrated in this study that trehalose prevented H(2)O(2)-induced autophagic death in SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation.